PH26788A - Chloroaniline derivatives - Google Patents

Description

Het represents a benzoheteroaryl or a monocyclic heteroaryl group wherein the heteroaryl group is 5 or 6 membered and contains 1, 2 or 3 hetero atoms, one of which is a nitrogen atom and the other(s) is (are) nitrogen, oxygen or sulphur atom(s), and the group Het may optionally be substituted by one or two groups selected from Cy-4alkyl, Cj_galkoxy, hydroxy, halogen, -NR3R%* and -coR8; where R3 ana gr? each represent a hydrogen atom or a Cy-4alkyl group or -NR3Rr% forms a saturated heterocyclic amino group which has 5-7 ring members and optionally contains in the ring one or more atoms selected from -0- or -S- or a group -NH- or -N(CH3)-: and

R8 represents hydroxy, Cj.galkoxy or -NR3R%; with the proviso that (i) when Het represents a pyridyl group substituted by the group -NR3R? or -cor® and Q is a chlorine atom, or (ii) when Het represents a pyridyl group optionally substituted by one or two groups selected from halogen, hydroxy, Cj-3alkyl and Cj-3alkoxy, and Y represents a bond or a Cj-4alkylene, Cp._galkenylene or Cay-galkynylene chain, then, in both cases, R represents a Ci-3alkyl group and/or at least one of the chains -XCHp~ and -CH,Y- is substituted by one or two Cj.jalkyl groups.

The compounds have a stimulant action at B2- adrenoreceptors and may be used in the treatment of diseases associated with reversible airways obstruction such as . asthma and chronic bronchitis.

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CHLOROANIL INE DERIVATIVES

This invention relates to chloroaniline derivatives having a : stimulant action at B,-adrenoreceptors, to processes for their : preparation, to pharmaceutical compositions containing them and to their use in medicine.

Chloroaniline derivatives have previously been described as bronchodilators having stimulant activity at p-adrenoreceptors.

Thus, British Patent Specification No. 1178191 describes compounds of the general structure

Hol ee R2

KN No erbores

HN x IE

Hal in which the substituents Hal represent bromine or chlorine atoms; R1 represents hydrogen or hydroxyl; R?2 and R3 each represent hydrogen or

C,-, alkyl; and RY and R® each represent hydrogen, Ci-¢ alkyl, ’ alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl, . ] cycloalkyl, phenyl, benzyl or adamantyl radicals, or NRYRS forms a } 20 heterocyclic ring optionally substituted by €,_; alkyl groups.

UK Patent Specification Nos. 2165542A and 2182658A describe compounds of the general structure cl \ oo } «—e R

Co 25 er ei gc 00h van -— oH R2 ; ’ oY } in which R! and R2 each represent hydrogen or Ci-3 alkyl; X represents

Co 30 © C,-¢ alkylene, C,_¢ alkenylene or C,_. alkynylene; Y represents C,_, ‘ alkylene, Coy alkenylene or Com alkynylene; and Ar represents a phenyl group optionally substituted by one or more of a variety of specific substituents.

We have now found a novel group of compounds which differ structurally from those Geseribed in British Patent Specification No. 1178191 and IK Patent Specification Nos. 21655424 and 2182658A, and which have a desirable and useful profile of activity.

Thus the present invention provides compounds of the general formula (I) \ .“_.o R RI

ZN lo]

Me J CHINHEXCH DCI Yet (1) «<e orn R2 cf and physiologically acceptable salts and solvates (e.g. hydrates) thereof, wherein

Q represents a chlorine atom or a trifluoromethyl group;

X represents a bond, or a Cig alkylene, Cog alkenylene or Coe alkynylene chain, and

Y represents a band, or a Cie alkylene, Cog alkenylene or Cog alkynylene chain with the proviso that the sum total of carbon atoms in the chains X and Y is not more than 10, and the chains XCH, and

CH,Y may each be optionally substituted by one or two Ci; alkyl groups, or, when one carbon atom is substituted by two alkyl groups, these may be linked to form an alkylene group;

R represents a hydrogen atom or a Cis alkyl group;

Rl and R? each represent a hydrogen atom or a C3 alkyl group, with the proviso that the sum total of carbon atoms in R! and R? is not more than 4; and

Het represents a benzoheteroaryl or a monocyclic heteroaryl group wherein the heteroaryl group is 5 or 6 membered and contains 1, 2 or 3 hetero atoms, one of which is a nitrogen atom and the other(s) represent nitrogen, oxygen or sulphur atom(s), and the group Het may optionally be substituted by one or two groups selected from Coy alkyl, Cy alkoxy, hydroxy, halogen, -NR3R% and -CORS; vhere R? and R" cach represent a hydrogen atom or a C1-yalkyl group or 3° -NR3R" forms a saturated heterocyclic amino group which has 5-7 ring members and optionally contains in the ring one or more atoms selected from -0- or -5- or a group -NH- or -N(CH 3) =; and

RS represents hydroxy, C,_, alkoxy or -NR3RY; : with the proviso that (i) when Het represents a pyridyl group ; 5 substituted by the group -NRIR* or -COR® and Q is a chlorine atom, or oh } (ii) when Het represents a pyridyl group optionally substituted by one goo o or two groups selected from halogen, hydroxy, C;_jalkyl and

Fi Cee C,-3elkoxy, and Y represents a bond or a C-yalkylene, C,_,alkenylene i) oo or C,_yalkynylene chain, then, in both cases, R represents a C;_3alkyl : 10 group and/or at least one of the chains -XCH,- and -CH,Y- is ‘ substituted by one or two C,_jalkyl groups. k It will be appreciated that the compounds of general formula (I) oo possess one or more asymmetric carbon atoms. The compounds according to the invention thus include all enantiomers, diastereoisomers and mixtures thereof, including racemates. Compounds in which the carbon atom in the -CH- group is in the R configuration are preferred.

OH

In the definition of general formula (1), the term alkenylene includes both cis and trans structures.

In the general formula (I), the chain XCH, may be for example “CH=, -(CHy),7, =(CHy) 3=, =(CHy) =, =(CH,) g-, =(CH,) (-, ~(CH,) ,-, -CH,C=CCH,~, ~(CH,) ,CH=CHCH,,-, -(CH,) ,C=CCH ,-, ~CH=CH(CH ,) ,-, ~CH=CH(CH, );- or -CH,C=C(CH,),~. The optionally substituted chain

CH,Y may be for example ~CH ,-, -(CH,) ,-, -(CH,) 5-, -(CH,) oy -(CHy)g~, =(CHy)g~, -CH(CH;)(CH,),=, -CH,CH=CH-, -CH,C=C=, -(CH,) ,CH=CH- or -(CH,),C=C-. - v bo Preferably the total number of carbon atoms ih the chains X and Y . is 4 to 10 inclusive. Compounds wherein the sum total of carbon atoms BE in the chains X and Y is 4, 5, 6, 7, B or 9 are particularly : preferred.

One preferred group of compounds of formule (I) is that in which

X represents a C3-,alkylene chain and Y represents a C,_calkylene r i chain. Particular compounds of this type are those wherein X ' 3 represents -(CH,),~ and Y represents ~(CH,) =, -(CH,), or -(CH,) 5-- ; 35 In the compounds of formula (1), R, R! and R2 may each be, for example, methyl, ethyl, propyl or isopropyl groups. If one of R! and

RZ is a propyl or isopropyl group, the other is a hydrogen atom or a methyl group. R, Rl and R? are cach preferably a hydrogen atom or a methyl group.

A preferred group of compounds are those in which R represents a hydrogen atom.

Another preferred group of compounds are those wherein R! and R2 are both hydrogen atoms, or R! is a hydrogen atom and R2 is a Ci-3 alkyl group, particularly a methyl group, or R! is a methyl group and

R? is a methyl group.

The group Het is attached to the rest of the molecule through any available position in the heteroaryl ring. Any substituent(d) in the group Het may be at any available position(s) in the benzene land/or the heteroaryl rings. Preferably tet represents a group selected from pyrimidinyl, pyrazinyl, triazinyl, thiszolyl, quinolinyl, benzimidezolyl, benzothiazolyl, benzoxazolyl and pyridyl.

A particularly preferred group of compounds of formula (I) is that in which Het represents a pyrimidinyl or thiazolyl group.

When the group Het is substituted by one or two halogen atoms, these may be chlorine, fluorine or bromine. When -NR3RY represents a saturated heterocyclic amino group, this may be, for example, a pyrrolidino, piperidino, hexamethyleneimino, piperazino,

N-methylpiperazino, morpholino, homomorpholino or thiamorpholino group.

Preferred compounds according to the invention are 4-amino-3,5- dichloro-a-[{[6-[4-(2-pyrimidinyl)butoxyJhexyllaminolmethyl] benzenemethanol; 4~amino-~3,5-dichloro-a~[[[6-[[6-(5~pyrimidinyl)hexylJoxy hexyl] amino Jmethyl]benzenemethanol; 4-amino-3,5-dichloro-a-[[[6-[[6-(2-pyrimidinyl)hexylJoxy Jhexyl] amino Jmethyllberzenemethanol ; 4-amino-3,5-dichloro-a-[[[6-[3-(2-thiazolyl)propoxy JhexylJamino] methyl Jbenzenemethanol; and their physiologically acceptable salts and solvates.

Suiteble physiologically accepteble salts of the compounds of general formula (1) include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulphates, :

phosphates, maleates, tartrates, citrates, henzoates, 4-methoxy- benzoates, 2- or 4-hydroxybenzoateg, 4-~-chlorobenzoates, benzene- sulphonates, p-tolucnesulphonates, naphthalenesulphonates, methanesulphonates, sulphamates, ascorbates, salicylates, acetates, diphenylacetates, triphenylacetates, adipastes, fumarates, succinates,

CL lactates, glutarates, gluconates, tricarballylates, hydroxy~naphthalenecarboxylates e.g. l-hydroxy- or 3-hydroxy-2- naphthalenecarboxylates, or oleates. The compounds may also form salts with suitable bases where appropriate. Examples of such salts are alkali metal (e.g. sodium and potassium) and alkaline earth metal (e.g. calcium or magnesium) salts, and salts with organic bases (e.g. triethylamine).

The compounds according to the invention have a stimulant action at f,-adrenoreceptors, which furthermore is of a particularly advantageous profile. The stimulant action was demonstrated in the isolated trachea of the guinea-pig, where compounds were shown to cause relaxation of contractions induced by PGF a or electrical . stimulation. Compounds according to the invention have shown a particularly long duration of action in these tests.

The compounds according to the invention may be used in the

Lo treatment of diseases associated with reversible airways obstruction such as asthma and chronic bronchitis.

So The compounds according to the invention are also indicated as oo i useful for the treatment of inflammatory and allergic skin diseases, . oo 25 congestive heart failure, depression, premature labour, glaucoma, and ; . ) in the treatment of conditions in which there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration. : Co The invention accordingly further provides compounds of formula . (I) end their physiologically acceptable salts and solvates for use in the therapy or prophylaxis of diseases associated with reversible airways obstruction in human or animal subjects.

The compounds according to the invention may be formulated for ] administration in any convenient way. The invention therefore includes within its scope pharmaceutical compositions comprising at least one compound of Formula (1) or a physiologically acceptable salt or solvate therenf formulated For use in human or veterinary medicine.

Such compositions may be presented for use with physiolngically acceptable carriers or excipients, optionally with supplementary medicinal agents.

S The compounds may be formulated in a form suitable for administration by inhalation or insufflation, or for oral, buceal, parenteral, topical (including nasal) or rectal administration.

Administration by inhalation or insufflation is preferred.

For administration by inhelatica the compounds according ta the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs, with the use of a suitable propellant, such as dichlorodifluoramethane, trichlorofluoromethane, dichlorotetrafluorocthane, carbon dioxide or other suitable gas, or from a nebuliser. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.

Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in For example capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.

For oral administration, the pharmaceutical composition may take the form of, for example, tablets, capsules, powders, solutions,

Syrups or suspensions prepared by conventional means with acceptable excipients.

For buccal administration Lhe composition may take the form of tablets, drops or lozenges formulated in conventional manner.

The compounds of the invention may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations . for injection may be presented in unit dosage form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the , active ingredient may be in powder form for reconstitution with a suitable vehicle, e.q. sterile pyrogen-frec water, before use.

For topical administration the pharmaceutical composition may take the form of ointments, lotions or creams formulated in a conventional manner, with for example an aqueous or oily base, generally with the addition of suitable thickening agents and/or " solvents. For nasal application, the composition may take the form of a spray, formulated for example as an aqueous solution or suspension or as an aerosol with the use of a suitable propellant.

The compounds of the invention may also be formulated in recta. compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or : other glyceride.

Where pharmaceutical compositions are described above for oral, buccal, rectal or topical administration, these may be presented in a conventional manner associated with controlled release forms.

A proposed daily dosage of active compound for the treatment of man is 0.005mg to 100mg, which may be conveniently administered in one or two doses. The precise dose employed will of course depend on the age and condition of the patient and on the route of administration.

Thus a suitable dose for administration by inhalation is 0.005mg to Co . 20mg, for oral administration is 0.02Zmg to 100mg, and for parenteral administration is 0.0lmg to 2mg for administration by bolus injection ~ and 0.0lmg to 25mg for administration by infusion.

The compounds according to the invention may be prepared by a | Lo } number of processes. In the following description, Q, X, Y, Het, R, ’ : R! and R? are as defined for general formula (I) unless otherwise specified. In the preparation of both intermediates and end-products i the final step in the reaction may be the removal of a protecting group. Suitable protecting groups and their removal are described in general process (3) below.

In one general process (1), a compound of general formulq (I) may , be prepared by ‘alkylation. Conventional alkylation procedures may be used.

Thus, for example, in one process (a), a compound af general

Formula (I) in which RY is a hydrogen atom may be prepared by alkylation of an amine of general formula (Ln) “\ .__.o R

Ne YN, cndirses (11) \ lo ee OH of (wherein R® is a hydrogen atom or a protecting group and R® is a hydrogen atom) followed by removal of any protecting group where present.

The alkylation (a) may be effected using an alkylating agent of general formula (III): ae Het (111) (wherein L. is a leaving group, for example a halogen atom such as chlorine, bromine or iodine, or a hydrocarbylsulphonyloxy group such as methanesulphonyloxy or p-toluenesulphonyloxy).

The alkylation is preferably effected in the presence of a suitable acid scavenger, for example, inorganic bases such as sodium or potassium carbonate, oryaniec bases such as triethylamine, diisopropylethylamine or pyridine, or alkylene oxides such ss ethylene oxide or propylene oxide. The reaction is conveniently effected in a solvent such as acetonitrile or an ether e.g. tetrahydrofuran or dioxan, a ketone e.g. butanone or methyl isobutyl ketone, a substituted amide e.g. dimethylformamide or a chlorinated hydrocarbon e.g. chloroform, at a temperature between ambient and the reflux temperature of the solvent.

According to another example (b) of an allylation process, a compound of general formula (1) in which R! represents a hydrogen atom : may be prepared by alkylation of an amine of general formula (11), as previously defined except that R® is a hydrogen atom or a group convertible thereto under the reaction conditions, with a compound of general formula (IV):

R2COXCH NCH, Y-tet (Iv) in the presence of a reducing agent, followed when necessary by removal . of any protecting groups. ) 5 Examples of suitable R® groups convertible into a hydrogen atom are arylmethyl groups such as benzyl, a-methylbenzyl and benzhydryl.

Suitable reducing agents include hydrogen in the presence of a catalyst such as platinum, platinum oxide, palladium, palladium oxide,

Raney nickel or rhodium, on a support such as charcoal, using an alcohol, e.g. ethanol or methanol, or an ester e.q. ethyl acetate, or an ether e.g. tetrshydrofuran, or water, as reaction sclvent, or a mixture of solvents, e.g. a mixture of two or more of those just described, at normal or elevated temperature and pressure, for example from 20 to 100°C and from 1 to 10 atmospheres.

Alternatively when one or both of R5 and R6é are hydrogen atoms, the reducing agent may be a hydride such as diborane or a metal hydride such as sodium borohydride, sodium cyanoborohydride or lithium aluminium hydride. Suitable solvents for the reaction with these . reducing agents will depend on the particular hydride used, but will include alcohols such as methanol or ethanol, or ethers such as diethyl

A ether or tert-butyl methyl ether, or tetrahydrofuran. : . , ‘Vhen a compound of formula (II) where RS and R® are each hydrogen atoms is used, the intermediate imine of formula (V) may be formed: , 25 nN [—— R

I Sethian foi tet (v) oe OH R2 cl

Reduction of the imine using the conditions described above, followed, where necessary, by removel of any protecting groups, gives a compound of general formula (1). . In another general process (2) compounds of Formula (1) may be prepared by reducing an intermediate of general formula (VI): - 1 - fo

Co :

il

No . Rt 7 \

Ney J EX AXEHL OCH Y He t (v1)

Tle R2 /

Cl wherein at least one of X1, X?, X and Y represents a reducible group and the other(s) take the appropriate meaning as Follows, which is x! is -CH(OH)-, X2 is —CHRNRS- (where RS represents a hydrogen atom or a protecting group), and X and Y are as defined in formula (1), followed where necessary by removal of any protecting groups.

Suitable reducible groups include those wherein X! is a group

Ye=0, X2 is a group -CHRNR”- (wherein R7 represents a group convertible to hydrogen by catalytic hydrogenation, for example an arylmethyl group such as benzyl, benzhydryl or a-methylbenzyl).

The reduction may be effected using reducing agents conveniently employed for the reduction of ketones or protected amines.

Thus, for example, when X! in general formula (VI) represents a

Je=0 group this may be reduced to a -CH(OH)- group using hydrogen in the presence of a catalyst such as platinum, platinum oxids, palladium, palladium oxide, Raney nickel or rhodium, on a support such as charcoal, using an alcohol e.q. ethanol, an ester e.g. ethyl acetate, an ether e.q. tetrahydrofuran, or water, as reaction solvent, or a mixture of solvents, e.g. a mixture of two or more of those Just described, at normal or elevated temperature and pressuré, for example from 20 to 100°C and from 1 to 10 atmospheres. Alternatively, the reducing agent may be, for example, a hydride such as diborane or a metal hydride such as lithium aluminium hydride, sodium bis(2-methoxyethoxy) aluminium hydride, sodium borohydride or aluminium hydride. The reaction may be effected in an appropriate solvent, such as an alcohol e.q. methanol or ethanol, or an ether such as tetrahydrofuran, or a halogenated hydrocarbon such as dichloromethane.

¥hen X2 in general formula (VI) represents a ~CHRNR 7 ‘ group this may be reduced to a -CHRNH- group using hydrogen in the presence of a catalyst as described above.

Co Co Where it is desired to use a protected intermediate of general pe . 5 formula (VI) it is particularly convenient to use a protecting group ol a RS which is capable of being removed under the reducing conditions, for example hydrogen and a catalyst, thus avoiding the need for a separate deprotection step. Suitable protecting groups of this type i include arylmethyl groups such as benzyl, benzhydryl and a-methylbenzyl.

In the above reduction process, and also in the preparation of intermediates, care must be taken to avoid the use of hydrogen and a catalyst when products are required in which X and/or Y represent alkenylene or alkynylene groups.

In a further process (3) compounds of formula (I) may be prepared by deprotecting an intermediate of general formula (vin) \ — R RL 7 \

HoN—ey + HICHNROGXCH ,0CH )Y-Het (VII) b <=e OH R2 : er wherein RS is a protecting group and/or the group Het contains a : protecting group. oo

The protecting group may be any conventional protecting group as : described for example in "Protective Groups in Dfganic Chemistry", by

Theodora Greene (John Wiley and Sons Inc, 1981). Thus, for example, hydroxy groups may be protected by arylmethyl groups such as benzyl, ' diphenylmethyl or triphenylmethyl, hy acyl groups such as acetyl, or as tetrahydropyraenyl derivatives. Examples of suitable amino : ’ protecting groups include arylmethyl groups such as benzyl, a-methylbenzyl, diphenylmethyl or triphenylmethyl, and acyl groups such as acetyl, trichloroacetyl or trifluoroacetyl.

The deprotection to yield a compound of general formula (I) may be effected using conventional techniques. Thus for example arylmethyl groups may be removed by hydrogenolysis in the presence of a metal catalyst (e.g. palladiom on charcoal). Tetrahydropyranyl groups may be cleaved by hydrolysis onder acidic condil ions. Acyl groups may ho removed by hydrolysis with an acid such as a mineral acid e.g. hydrochloric acid, or a base such as sodium hydroxide or potassium carbonate, and a group such as trichloroacetyl may be removed hy reduction with, for example, zin: and acetic acid.

Intermediates of formula (VI) for use in the reduction process (2) in which X! is the group p= may he prepared by reaction of a haloketone of formula (VIII) | \ — R non Nobel (VIII)

TN

«e cr’

LS (where tal represents a halogen atom e.g. bromine) with an amine of formula (IX) it

RSNICXCH OCH YV-Het (IX) v2 (where RS is a hydrogen atom or a group convertible thereto by catalytic hydrogenation).

The reaction may be effected in a cold or hot solvent, for example tetrahydrofuran, tert-butyl methyl ether, dioxan, chloroform, dichloromethane, dimethylformamide, acetonitrile, a ketone such as butanone or methylisobutylketone, or an ester such as ethyl acetate, preferably in the presence of a base such as diisopropylethylamine, sodium carbonate or other acid scavenger such as propylene oxide.

Intermediates of general formula (VI) in which X! is the group

Ses may be reduced to the corresponding intermediate in which X! is the group -CH(OH)- using for example a metal hydride such as sodium borohydride in a solvent e.g. ethanol, methanol and/or tetrahydrofuran.

Amines of formula (11) and haloketones of formula (VIII) are either known compounds or may be prepared by methods analogous to those described for the preparation of known compounds. n Suitable methods for preparing intermediates of formulae (III), 0 5 (IV) and (IX) are described in UK Patent Specifications Nos. 2140800A

H and 2159151A end in the exemplification included hereinafter. oo In the general processes described above, the compound of formula

Co (1) obtained may be in the form of a salt, conveniently in the form of . a physiologically acceptable salt. Where desired, such salts may be converted to the corresponding free bases using conventional methods.

Physiologically acceptable salts of the compounds of general formula (I) may be prepared by reacting a compound of general formula (I) with an appropriate acid or base in the presence of a suitable solvent such as acetonitrile, acetone, chloroform, ethyl acetate or an alcohol, e.g. methanol, ethanol or isopropanol.

Physiologically acceptable salts may also be prepared from other salts, including other physiclogically acceptable salts, of the ) compounds of general formula (I), using conventional methods.

When a specific enantiomer of a compound of general formula (I) is required, this may be obtained by resolution of a corresponding racemate of a compound of general formula (I) using conventional methods. :

Thus, in one example an appropriate optically active acid may be : Co used to form salts with the racemate of a compound of general formulas (I). The resulting mixture of isomeric salts may be separated for i example by fractional crystallisation, into the diastereoisomeric salts from which the required enantiomer of a compound of general formula (I) may be isolated by conversion into the required free base. oo 30 Alternatively, enantiomers of a compound of general formula (I) may be synthesised from the appropriate optically active intermediates . using any of the general processes described herein. : Specific diastereoisdmers of a compound of formula (I) may be obtained by conventional methods for examplé, by synthesis from an appropriate asymmetric starting material using any of the processes described herein, or by conversion of a mixture of isomers of a compound of general formula (I) into appropriate diastereoisomeric derivatives e.g. salts which then can be separated by conventional means e.g. by fractional crystallisation.

The following examples illustrate the invention. Temperatures are in 9C. 'Dried' refers to drying of organic extracts using magnesium sulphate or sodium sulphate. Unless otherwise stated, thin layer chromatography (t.l.c.) was carried out on silica and flash column chromatography (FCC) on silica (Merck 9385) using one of the following solvent systems : A-toluene:ethanol:0.88 ammonia,

B-toluene:ethanol:triethylamine, C-diethyl ether:methanol. The following abbreviations are used : THF - tetrahydrofuran, OMF - dimethylformamidé, BTPC - bis(triphenylphosphine)palladium (11) chloride, TAB ~ tetra-n-butylammonium hydrogen sulphate, DEA -

N,N-diisopropylethylamine.

Intermediate 1 is 1-(4-amino-3,5-dichlorophenyl )-2-bromoethanone .

Intermediate 2 is 4-amino-a-(aminomethyl)-3,5-dichlorobenzenemethanol.

Intermediate 3 4-(2-Pyrimidinyl)-3-butynol

A mixture of 2-bromopyrimidine (5.0g), 3-butynol (2.20q), dicyclohexylamine (6.879), copper (I) iodide (50mg), BTPC (380mg) and acetonitrile (50mf) was stirred at room temperature under nitrogen for 16h. Ether (150m2) was added, the mixture filtered and the filtrate evaporated in vacuo. Purification of the residue by FCC eluting with ether and ether-methanol (1-3%) followed by System C (5:1) afforded the title compound as a pale yellow solid (4.29g) m.p. 58-640, t.1.c. (System C, 99:1) Rf 0.08

Intermediate 4 6-(2-Pyrinidinyl)-5-hexynol : A mixture of 2-bromopyrimidine (3.96g), S5-hexynol (2.44g), dicyclohexylamine (4g), BTPC (250mg), copper (1) iodide (25mg) and acetonitrile (40mR) was stirred abt ambient temperature under nitrogen for 1h (temp. rose to ~45%). Fther (120m) was added, the mixture was filtered and the filtrate was evaporated in vacuo to an oil which was 3 purified by FCC. Clution with ether followed by System C (17:3) gave g the title compound as a pale yellow oil (3.64q), t.l.c. (System C id cs 17:3) Rf 0.34.

RE Intermediate 5 : 6-(5-Pyrimidinyl)-5-hexynol

A mixture of S-bromopyrimidine (3.969), S5-hexynol (2.44q), dicyclohexylamine (4g) and acetonitrile (50m2) was de-oxygenated by bubbling nitrogen through the solution for 10min. BTPC (150mg) and copper (I) iodide (25mg) were added and the mixture was heated to 60-700 under nitrogen for lh, cooled and evaporated in vacuo. Ether (175m) was added, the mixture filtered and evaporated in vacuo and : the residue purified by FCC. Elution with ether followed by System C (19:1-92:8) gave the title compound as a pale yellow oil (3.79q), t.l.c. (System C (17:3) Rf 0.55.

Intermediate 6 2-Pyrimidinebutanol bras ot nessa

Stn 20 eg (2-Pyrimibing 1) <3: bubyiol (159) in “ethanol “(4Bni) was added to pre-reduced 10% palladium on charcoal (50% aqueous paste) in ethanol (60m) and hydrogenated at room temperature and atmospheric pressure.

The catalyst was removed by filtration through hyflo and the solvent evaporated in vacuo. The residual oil was purified by FCC. Elution with System C (19:1) and (9:1) gave the title compound as a pale yellow oil (1.32g)

Analysis Found: C,63.1; H,7.7; N,18.1.

CgHy,N,0 requires C,63.1; H,7.95; N,18.4%.

Intermediate 7 . 2-Pyrimidinehexanol : A solution of 6~(2-pyrimidinyl)-S-hexynol (3.099) in ethanol : (100mg) wast added to a pre-hydrogenated suspension of 10% palladium on charcoal (1.05g) in ethanol (50m) and hydrogenated at room temperature and pressure, filtered and evaporated in vacuo. The residual oil was purified by ICC eluting with ether and System C (99:1-85:15) to give the title compound as a pale yellow oil (0.93q).

Analysis ound: C,66.485 1,91; Ny15.6;

CiglygN,0 requires C,66.6; H,8.95; N,15.5%

Intermediate 8 5-Pyrimidinehexanol

A solution of 6-(5-pyrimidinyl)-5-hexynol {(3.52g) in ethanol (20m) was added to a pre-hydrogenated suspension of 10% palladium on carbon (1g) in ethanol (130m%) and hydrogenated at room temperature and pressure. The mixture was filtered through hyflo and the filtrate evaporated in vacuo to nive the title compound as a pale yellow oil (3.384).

Analysis Found: C,66.6; 11,9.0; N,15.2;

Cot eN,0 requires €,66.6;5 H,8.95; N,15.5%.

Internediate 9 1-(Phenylmethyl)-2-benzimidazolepropanol

A mixture of 2-benzimidazolepropanol (3.52qg), benzyl bromide (2.38m) and anhydrous potassium carbonate (5.52qg) in acetonitrile (57m1) was stirred at reflux far 4h, after which time more benzyl bromide (0.24mt) was added. The mixture was stirred at reflux for a further 2h, cooled, diluted with water (200m), extracted with ethyl acetate (2x100m2) and the organic extracts dried and evaporated in vacuo to give an orange oil. Purification by FCC eluting with System

B (98:2:1) gave a colourless oil (4.3g) which solidified on standing to give the title compound as a white solid (4.3g), t.l.c. (System A 40:10:1) RF 0.41.

Intermediate 10 2-Benzoxazoleethanol

A mixture of 2-methylbenzoxazole (4.0g) and paraformaldehyde (1.35q) was heated at 1400 with stirring in a 25m2 autoclave for 3h. ’

The mixture was cooled and the residue purified by I'CC. Elution with hexane-ether (2:1-1:1) followed by ether and ether-methanol (1-5%) afforded a product (1.89) which was distilled b.p. 165-1709/0.4mmltg

(Kugelrohr) to give the title compound as a colourless solid (1.226qg) m.p. 47-520, t.l.c. (ether) Rf 0.73. d Intermediate 11 wo 5 2-[4-[(6-Bromohexy1)oxy butyl Jpyrimidine : A mixture of 2-pyrimidinebutanal (1.319), 1,6-dibromohexane (5m2), 50% aqueous sodium hydroxide solution (5mf) and TAB (140mg) was _. vigorously stirred under nitrogen at 23% for 20h. Ether (25mg) and water (20mf) were added, the organic phase separated, washed with brine (20mg), dried and evaporated in vacuo. The residue was purified by FCC. Elution with hexane and hexane-ether (9:1) followed by ether afforded the title compound as a colourless oil (1.67q)

Analysis Found: C,53.3; H,7.2; N,8.9.

Cy, Hy3BIN,0 requires C,53.3; H,7.3S; N,8.9%.

Intermediate 12 4-02-[(6-Bromohexyl)oxyJethyl]-2-methylthiazole

A mixture of 2-methyl-4-thiazoleethanol (2.229), 1,6- dibromohexane (7.1mg) 12.5M aqueous sodium hydroxide (4m2) and TAB (0.1g) was stirred rapidly at room temperature for 16h. The reaction mixture was diluted with water (30m2), extracted with ether (3x30m2) and the combined organic extracts were washed with water (30m) and brine (30m), dried and concentrated. The residual oil was purified by FCC eluting with diethyl ether-hexane (1:3) to give the title compound as an orange oil (2.21g), t.l.c. (ether - hexane 1:3) Rf 0.17

Intermediate 13 2-[2-[(6-Bromohexy1)oxyJethylJbenzoxazole

A mixture of 2-benzoxazoleethanol (1.4649), 50% sodium hydroxide } (3m), 1,6-dibromohexane (3m2), TAB (100mg) and dichloromethane (2m) . was vigorously stirred at room temperature for 22h, diluted with water (15me) and extracted with ether (40mL). The organic phase was washed with brine (10mg), dried and evaporated in vacuo. The residual oil was purified by FCC. Elution with hexane and hexanc-ether (19:1)

followed by hexane-ether (2:1) and ether gave the title compound as a pale yellow oil (1.60q) which solidified on refrigeration.

Analysis Foun: C,50. 8; 11,6.0; N, 4.35.

CgHygBrNO, requires €,55.2; H,6.2; N,4.3%.

Intermediate 14 2-[6-[(6-Bromohexyl)oxy Jhexyllpyrimidine

A mixture of 2-pyrimidinehexanol (1.18q), 1,6-dibromohexane (4me), 50% sodium hydroxide (4m2) and TAB (100mg) was vigorously 1c stirred at room temperature for 17h, then diluted with water (40m) and ether (50mg). The organic phase was dried and evaporated in vacuo to an oil which was purified by FCC. Flution with hexane followed by hexane-ether (1:1) gave the title compound as a colourless oil (670mg), t.l.c. (ether) Rf 0.24

Intermediate 15 5-16-[(6-Bromohexyl)oxyJhexyllpyrimidine

A mixture of S-pyrimidinehexanol (1.82g), 50% sodium hydroxide (6m2), 1,6-dibromohexsne (6m%) and TAB (150mg) was vigorously stirred at room temperature for 3Dh then diluted with water (20mf) and ether (25m). The organic phase was dried and evaporated in vacuo. The residue was purified by FCC eluting with hexane followed by hexane-ether (1:1) and ether, to give the title compound as a colourless liquid (2.21g), t.l.c. (ether) Rf 0.35.

Intermediate 16 2-12-[ (5-8romopentyl)oxylethyllquinoline 2-(2-Hydroxyethy l)quinoline (2.00q), TAB (200mg) and 1,5-dibromopentane (8m) were dissolved in dichloromethane (6m) and 50% aqueous sodium hydroxide (8m) added. The mixture was vigorously stirred at room temperature for 26h, diluted with water (50m2) and extracted with diethyl ether (2x30m2). The organic extracts were dried, filtered and evaporated in vacuo to afford an oil, which! was purified by FCC eluting with cyclohexane-ether (1:1) and ether, to give the title compound as a yellow oil (2.67g), t.l.c. (ether) Rf 3.40.

— —

Intermediate 17 2-(3-[ (5-Bromopentyl)oxyJpropyll-1-(phenylmethyl)benzimidazole

A mixture of 1-(phenylmethyl)-2-benzimidazolepropanol . (3.0g), 1,5-dibromopentane (7.77g), TAB (0.5q) and 40% sodium + 5 hydroxide (5m2} in dichloromethane (10mf) was stirred at room temperature for 6h under nitrogen. The mixture was diluted with water " (100mg) and extracted with dichloromethane (2x100mf). The dried extracts were evaporated in vacuo to give an oil. Purification by FCC eluting with hexane-ether (10:0+0:10) gave the title compound as a colourless oil (0.98qg).

Analysis Found: C,63.30; H,6.54; N,6.76. ) C,,l,,BIN,0 requires C,63.61; 1,6.55; N,6.74%.

Intermediate 18 2-[3-[ (5-Bromopentyl)oxylpropyl]-1H-benzimidazole

A solution of 2-[3-[(5-bromopentyl)oxylpropyl]-1-(phenylmethyl) benzimidazole (1.7g) in absolute ethanol (20m%) containing 1:9 conc. hydrochloric acid:ethanol (3.27m%) was hydrogenated over pre-reduced 10% palladium oxide on charcoal catalyst (3Q0Omg) in ethanol (5m2) until the uptake of hydrogen (10lm2) ceased. The mixture was filtered . through hyflo and evaporated in vacuo to give an oil, which was dissolved in ether (150m) and washed with 8% sodium bicarbonate solution (100mg), dried end evaporated in vacuo to give an oil.

Purification by FCC eluting with hexane-ether (2:3+0:5) gave the title oo 25 compound as a yellow oil (0.92g). ) Analysis found: C,55.1; H,6.55; N,B.6.

C,sH,,BIN,0 requires C,55.4; H,6.5; N,B8.6%.

Intermediate 19 } 30 N-[6-[2-(2-Benzoxazolyl)ethoxylhexyl]benzenemethanamine : , : - A solution of 2-[2-[{6-bromohexyl)oxylethyl]lbenzoxazole (1.55q) in benzylamine (6mt) was heated at 125% for 2h under nitroger, cooled, } ! diluted with ether (100m%) end the ether suspension washed with 8% sodium bicarbonate solution (25m). The organic phase was dried and evaporated in vacuo. Benzylanine was removed by bulb to bulb distillation (b.p. 130%/25mm) to leave a product which wes purified by ’ ! » - 21 - wooo chramatography over silicon (Hercic ol) elaling vith Syastom 8 (82:10:10) to afford the title compound as a red oil (250mg), t.l.c. (System A 39:10:1) RF 0.55.

Intermediate 20 4-Amino-3,5-dichloro-a-{{[6-[2-(2-benzoxazolyl)ethoxy Jhexyl] {phenylmethyl)aminolmethyl]benzenemethanol

A solution of Intermediate 1 (1.16g), N-[6-[2-(2-benzoxazolyl) ethoxy JhexylJbenzenemethananine (1.469) and DEA (0.78m%) in THF (50m) was allowed to stand for 6h, then filtered and evaporated in vacuo.

The residual gum in methanol (20m%) was cooled to 0-59 and sodium borohydride (650mg) added portionwise over 0.5h. After a further 0.5h at 50 the solution was evaporated in vacuo and the residue partitioned between water (30mf) and ethyl acetate (60m2). The organic phase was dried and evaporated in vacuo to a gum. The residue was purified by

FCC eluting with hexane-ethyl acetate-triethylamine (60:40:1) to give the title compound as a pale yellow oil (1.10g), t.l.c. (hexane- ethyl acetate 2:1) RF 0.21.

Intermediate 21 : 2-[2-[ (6-Bromohexyl)oxylethyl]pyridine

A mixture of 2-pyridineethanol (5g), 1,6-dibromohexane (20m%), 50% (w/v) sodium hydroxide (20mg) and TAB (500mg) was stirred at room temperature for 6h. Water (100m) was added and the mixture was extracted with ether (2 x 100mg). The organic extracts were washed with water and brine, dried and concentrated to an oil which was purified by FCC eluting with hexaneshexane-ether (1:1) to give the title compound as a colourless oil (6.6g), t.l.c. (hexane-ether 1:1)

Rf 0.19.

Intermediate 22

N-16-[2-(2-Pyridinyl)ethoxy Ihexyl]lvenzenemel hanamine

Bh 2-[2-[ (6-Bromohexyl)oxy Ji:thyllpyridine (6.3) ‘was added to benzylamine (20m2) at 140% under nitrogen. After lh at 1409 the reaction mixture was cooled and partitioned between 2H sodium hydroxide (100m) and ether (100mZ). The organic layer was washed - 22 -

S—

RAD ORIGINAL P with water and brine, dried and concentrated to a yellow oil. The excess benzylamine was removed by distillation under reduced pressure } Ce to leave the title compound as a yellow oil (6.8g), t.l.c. (System A

Ca 80:20:2) RF 0.44.

Ls a Co Intermediate 23 4-Amino-3,5-dichloro-a-[1-[ (phenylmethyl)[6-({2-(2-pyridinyl)ethoxy] hexylJamino]ethyl]benzenemethanol

A solution of 1-(4-amino-3,5-dichlorophenyl)-2-bromopropanone : 10 (1.12qg), N-[6-[2-(2-pyridinyl)ethoxylhexylJbenzenemethanamine (1.18g) and DEA (0.92me) in THF (20m2) was heated at reflux for 20h under nitrogen, then cooled to 0-59 for lh. The mixture was Filtered and the filtrate evaporated in vacuo to a dark oil which was taken up in methanol (20me) and cooled to 0-50. Sodium borohydride (570mg) was added portionwise over 20 min, the solution allowed to warm to 200 over 2h and evaporated in vacuo. The residue was partitioned between water (50m) and ethyl acetate (100m2) and the organic phase dried and evaporated in vacuo to a qum. Purification by FCC eluting with hexane-ethyl acetate (2:1-1:1) gave the title compound as a colourless gum (680mg), t.l.c. (hexane-ethyl acetate 2:1) Rf 0.15.

Intermediate 24 a-Methyl-2-pyridinepropanol

Dimethyl sulphoxide (3.3m) was added dropwise to a solution of oxalyl chloride (3.9m2) in dichloromethane (25m%) at ~78°% under nitrogen. After gas evolution had ceased (5min) a solution of 2-pyridinepropanol (4.09) in dichloromethane (20m) was added over 5min and the solution stirred at -78% for 20min. Triethylemine (5m) was added dropwise to the solution, then the resulting dark green mixture warmed to 209 and washed with 2M sodium carbonate solution (20m). The organic phase was dried and evaporated in vacuo to give 2-pyridinepropanal. This aldehyde was immediately dissolved in THF (30m2) and edded dropwise to a 3H solution of methylmagnesium chloride in THF (20mg) at 0-5% under nitrogen. After lh, water (10m%) was cautiously added followed by sufficient 2H hydrochloric acid to dissolve all the magnesium residues (resulting pi~7). The solution was extracted with dichloromethane (3 x 30m) and the organic extracts dried and evaporated in vacuo to a dark oil. Kugelrohr bulb to bulb distillation (b.p. 130-135%/0.7mm) afforded the title compound as a pale yellow oi! (0.91g), t.l.c. ethyl acetate Rf 0.17.

Intermediate 25

N-[6-[1-Methyl-3-(2-pyridinyl)propoxylhexyl]benzenemethanamine - A mixture of a-methyl-2-pyridinepropanol (0.62qg) 1,6-dibromohexane (4mg), 50% sodium hydroxide (4mf) and TAB (50mg) was vigorously stirred at 500 for 6h, cooled and diluted with water (15m2) snd ether (100mg). The ether extract was dried and evaporated in vacuo to an oil which was partitioned between 2N hydrochloric acid (60mg) and hexane (2x25m%). The acidic aqueous phase was basified with 40% sodium hydroxide to pHl2 and extracted with ether (2x50m2).

The ethereal extracts were dried and evaporated in vacuo to give 2-[3-[(6-bromohexyl)oxy]-1- methylpropyllpyridine (360mg) as a : colourless oil. This was dissolved in benzylamine (4m), and heated at 1259 for 2h under nitrogen, cooled and combined with an earlier reaction product (from 0.28yg of the bromo compound) and partitioned hetween B% sodium bicarbonate solution (40m) and ether (100m). The ether phase was dried and evaporated in vacuo. Benzylamine was removed by distillation in vacuo (Kugelrohr 1509/25mm) to leave the title compound as a yellow oil (0.68g), t.l.c. (System A 39:10:1) Rf 0.36. :

Intermediate 26 4-Amino-3,5-dichloro-a-[[[6-[1-methyl-3-(2-pyridinyl)propoxyJlhexyl]- (phenylmethyl)amino]methyl]benzenemethanol

A solution of Intermediate 1 (0.6g) and DEA (0.55m%) in THF (20m2) was treated with ‘N-[6-[1-methyl-3-(2-pyridinyl)propoxy]- hexyl Jbenzenemethanamine (0.729) and the solution allowed to stand for 7h, then filtered and evaporated in vacuo. The residue in methanol (15m2) was cooled to 0-59 and sodium borohydride (0.42g, 11.1lmmol) added portionwise over 20min. After lh, the solution was evaporated in vacuo and the residue partitioned between water (15mf) and ethyl acetate (60mf). The organic phase was washed with brine (10mf), dried and evaporated in vacuo to a pale yellow gum which was purified by FCC eluting with hexane-ethyl acetate-triethylamine (66:33:1) to give the title compound as a pale yellow gum (0.91g), t.l.c. (diethyl ether) a. Rf 0.38.

Cs

Cyc Intermediate 27 dire cE © [6-[(6-Bromohexyl)oxyl-1-hexynyllpyrazine

Alp ee ~ A mixture of bromopyrazine (1.64g), 6-[(6-bromohexyl)oxy]-1-hexyne

Sa oo ; (2.69g) N,N-dicyclohexylamine (1.88g), BTPC (130mg) and copper (I)

Sh 10 iodide (13mg) in acetonitrile (30mi) was stirred at 220 under nitrogen

Co for lh. Ether (150mg) was added, the mixture filtered and evaporated oo in vacuo to an oil which wes purified by FCC eluting with hexane-ether (3:2 » 1:1) followed by ether to give the title compound as a dark yellow oil (2.79q), t.l.c. (ether) Rf D.5.

Intermediate 28 [6-[ (6-Bromohexyl)oxyJhexyllpyrazine

A solution of [6-[(6-bromohexyl)oxyl-l-hexynyllpyrazine (2.76g) in ethanol (70mt) was added to a pre-hydrogenated suspension of 10% : © 20 palladium on carbon (2.00g) in ethanol (50m%) and hydrogenated at room temperature and pressure for 1lh. The mixture wes filtered through

I .. hyflo end evaporated in vacuo to afford the title.compound ag.a* ™ ". ~~ '%7 "0 3 colourless oil (2.45g), t.l.e. (ether) Rf 0.55.

Intermediate 29 3-{(2-Thiazolyl)]-2-propynol

Copper (I) iodide (28.5mg) was added to a stirred solution of 2-bromo- thiazole (5g), propargyl alcohol (1.68g), BTPC (210mg) and DEA (2.41q) i in acetonitrile (88m&). The mixture was stirred under nitrogen for

BOh, concentrated and partitioned between ethyl acetate (100mg) and i water (100mf). The organic layer was dried and concentrated to yield . : the crude product which was purified by FCC eluting with toluene/ethyl ] acetate (5:2) to give the title product ss a brown oil (0.68g), 4 - t.l.c. (toluene/ethyl acetate 2:1) Rf 0.27. io 35

ANE j - { _ 25 - oo “

- ! *

Intermediate 30 i 2-Thiazolepropanol

Glacial acetic acid (16m) was added dropwise during 0.25h to a stirred solution of 3-(2-thiazolyl)-2-propynol (2.4q) and dipotassium ‘ 5 azodicarboxylate (50g) in pyridine (200m%). The mixture was stirred : at room temperature for lh and additional glacial acetic scid (40mg) ’ ; . added during 0.5h. The mixture was stirred at room temperature for 2 days. The solvent was removed by azeotropic distillation with toluene (2x100m2) and the residue partitioned between water (100m2) and ethyl acetate (100mt). The aqueous layer was extracted with ethyl acetate (2x50m2) and the combined extracts dried and evaporated to leave a brown oil. This was purified by FCC eluting with toluene:ethyl i acetate:triethylamine (50:50:1) to give the title compound as an orange oil (1.45g), t.l.c. (toluene:ethyl acetate:triethylamine 50:50:1) Rf 0.15.

Intermediate 31 2-[[(6-Bromohexyl)oxylpropyl]thiazole

A mixture of 2-thiazolepropanol (1.45g) 1,6-dibromohexane (7.4qg), TAB (125mg) and 50% w/v sodium hydroxide solution (5mf) was stirred at room temperature for 6h, diluted with water (50m%) and extracted with ether (3x50mf). The combined, dried extracts were evaporated and the residue was purified by FCC eluting with toluene followed by System B (98:2:1), to give the title compound as a pale yellow oil (1.76qg), t.l.c. (System B 95:5:1) Rf 0.55.

Intermediate 32 6-[ (6-Bromohexyl)oxy]-1-hexyne

A mixture of 5-hexyn-l-ol (5g), 1,6-dibromohexane (37.29g), TAB (lg) and 50% sodium hydroxide solution (20mg) was stirred under nitrogen for 22h. The mixture was diluted with water (100m) and extracted with diethyl ether (2 x 150m&). The combined organic extracts were } dried and evaporated in vacuo to give an cil. Purification by FCC eluting with hexane followed by hexane:ether (95:5) gave the title compound as a colourless nil. (7.7g), t.l.c. {(hexane:ether 2:1) Rf 0.80. . - 26 -

J

Intermediate 33 2-[6-[(6-Bromohexyl)oxy]-1-hexynyllquinoline

A mixture of 2-bromoquinoline (3.00g), 6-[(6-bromohexyl)oxy]-1-hexyne (3.77g), BTPC (90mg), copper (I) iodide (1lmg) and dicyclohexylamine (2.799) in acetonitrile (35mf) was stirred at room temperature under - nitrogen for 20h. The mixture was diluted with ether (90mg), filtered and the filtrate evaporated in vacuo to give a brown oil.

Purification by FCC eluting with hexane:ether (4:1 + 2:1) gave the title compound as a brown oil (4.25g), t.l.c. (hexane:ether 2:1) Rf 0.22. .

Intermediate 34

N-[6-[[6-(2-Pyridinyl)-5-hexynyl]oxylhexy! Jbenzenemethanamine

A mixture of 2-bromopyridine (2.67g), 6-[(6-bromohexyl)oxy]-l-hexyne (4.41g), BTPC (105mg), copper (I) iodide (13mg) and N,N- dicyclohexylamine (3.37g) in acetonitrile (40mf) was stirred at room temperature under nitrogen for 20h. The mixture was diluted with h ether (100m), filtered and the filtrate evaporated in vacuo to give e brown oil. Purification by FCC eluting with hexane:ether (9:1 + 1:1) gave a brown oil (4.59g) which was heated with benzylamine (13.8m%) at 1009 for 2.5h. The mixture was washed with B% sodium bicarbonate solution (75m2) and ether (75m2). The combined organic extracts were dried and evaporated in vacuo and excess benzylamine was removed by : distillation in the Kugelrohr apparatus to leave the title compound as a brown oil. (3.60g), t.l.c. (System A 40:10:1) Rf 0.58. :

Intermediate 35 4-Amino-3,5-dichloro-a-[{ (phenylmethyl)[6-[[6-(2-pyridinyl)-5- hexyny1]oxy Jhexyl]amino]lmethyl]benzenemethanol "A solution of l-[4-amino-3,5-dichlorol-2-bromoethanone (0.93g) and

N-[6-[[6~(2-pyridinyl)-5-hexynylloxy Jhexyllbenzenemethanamine (1.29) in THF (30mg) was stirred under nitrogen for 20h. The mixture was . filtered and the filtrate evaporated in vacuo to give an oil. The oil was dissolved in methanol (25m) and dichloromethane (35m2) and sodium borohydride (0.51g) added portionwise to the solution at 00 under nitrogen. The solution was stirred at room temperature for 1h, then carefully diluted with water (12m%) and evaporated in vacuo. The residue was partitioned between ethyl acetate (100m%) and water (100me), the aqueous phase was re-extracted with ethyl acetate (100mg) and the combined organic fractions dried and evaporated in vacuo to give a brown oil. Purification by FCC eluting with } hexane:ethyl acetate (1:1) gave the title compound as an orange-brown

Eh oil (1.65g), t.l.c. (hexane:ethyl acetate 1:1 on 2% triethylamine

Ts doped plate) Rf 0.61. Co

Intermediate 36 2-[3-{ (6-Bromohexy1)oxyIpropyllyuinoline 2-Quinolinepropanol (0.92g), 50% aqueous sodium hydroxide (Sm%), 1,6-dibromohexane (5m) and TAB (57mg) were vigorously stirred at 210 for 6h. The mixture was diluted with water (25m%) and ether (100m%) and the organic phase dried and evaporated in vacuo. The residue was purified by FCC with hexane eluant to remove 1,6-dibromohexane.

Elution with ether afforded the title compound as a yellow oil (0.88g), t.l.c. ether Rf 0.51.

Example 1 4-Amino-3,5-dichloro-a-[{[6-{4-(2-pyrimidinyl)butoxy]hexyl]amino]- methyl]lbenzenemethanol

A mixture of Intermediate 2 (0.84g), 2-{4-[(6-bromohexyl)oxy] butyllpyrimidine (0.80g), DEA (0.53m%) and DMF {(10m2) was heated at

CTY 28 1600 Fer 1h under nitrogen. The solution was cboled, evaporated in = ' vacuo, end the residue purified by FCC eluting with System A (88:10:1). The resulting product was dissolved in hot isopropanol . (15m&) containing fumaric acid (90.5mg), cooled and kept at 0° for 1h

The crystalline, hygroscopic hemifumarate salt was collected by - 30 filtration. The mother liquors deposited a second crop which was combined with the first crop, and partitioned between 8% sodium ' bicarbonate solution (60m) and ethyl acetate (2x60mf). The combined . : organic extracts were dried and evaporated in vacuo to a gum. ’ 35 ¢

Co . - 28 -

a —

Trituration with hexane (20m) for 24h afforded the title compound as a colourless powder (440mg), m.p. 77-799, t.l.c. (System A 39:1N:1) Rf 0.46.

Analysis Found: C,57.5; H,7.2; N,12.0; Cl,15.6.

C,,H3,C1,N,0, requires C,58.0; 1,7.15 N,12.3; £1,15.6%. ne Examples 2-4 were prepared in a similar manner from Intermediate 2 and the appropriate bromo compound.

Exemple 2 4-Amino-3,5-dichloro-a-[ [[5-(2-quinolinylethoxy)pentylJamino]methyl]- benzenemethanol, (E)-butenedioate salt (2:1)

From Intermediate 2 (1.00g) and 2-[2-[(5-bromopentyl)oxylethyl] quinoline (0.97g). The product from FCC (eluting with System A (44:5:1) and (39:10:1)) was dissolved in ethyl acetate (60mg), washed with B% sodium bicarbonate solution (30mg), brine (30m%), dried and evaporated in vacuo. The residual gum (~1g) was dissolved in hot isopropanol (12m) and treated with fumaric acid (125mg). The hot solution was filtered and the crystals which deposited on cooling were collected by filtration. A further recrystallisation from isopropanol (20m) afforded the title compound (0.71q) m.p. 140-1439 (after being dried at 500/lmm Hg for 6h.), t.l.c. (System A 39:10:1) RF 0.52.

Analysis Found: C,58.9; H,5.9; N,7.65; €l1,14.2.

CpuHygC1,N;0,0-5C, 1,0, -0.05CHg0.0. 41,0 requires c,59.2; H,6.1; N,7.9% C1,13.4%.

Example 3 4-Amino-3 ,5-dichloro-g-[[[6=[2-(2-nethyl-4-thiazolyl)ethoxy hexyl] aminolmethyl]benzenemethanol

From 4-[2-[ (6-bromohexyl oxy lethyl]-2-methylthiazole (1.2q) and

Intermediate 2 (1.309), heating the reaction mixture for 1l.5hr. FCC eluting with System B (97:3:1) gave an oil which when triturated with hexane gave the title compound 8s a white solid (0.78g) m.p. 67-690.

Analysis Found: €,53.9; H,6.6; N,9.3; c1,15.7; S,7.2. . 35 C,oH,9C1,N;30,S requires c,53.8; H,6.6; N,9.4; C1,15.9; S,7.2% a - 29 - Co

Example 4 4-Amino-3,5-dichloro-a-[[[5-[3-(Lii-benzimidazol-2-y1l)propoxy pentyl] amino]methyl]l:znzenemethanol, (E)-butencdioate salt (2:1)

From Intermediate 2 (0.87g), and 2-[3-[ (5S-bromopentyl)oxy]

S propyl]-li-benzimidazole (0.85g), heating the reaction mixture for 3h. } FCC eluting with System B (95:5:1) gave a brown oil which was 4 dissolved in methanol (15m%) end treated with fumaric acid (0.08g).

B ; The solution was evaporated and triturated with diethyl ether to give 3 an orange solid. Treatment with hot isopropanol-ether (ca 1:4) followed by evaporation in vacuo gave a yellow foam, which was dried in vacuo at ca 40° for 10h to ive the title compound as a yellow solid (335mg) m.p. 55-600 (decomp), t.l.c. (System A 40:10:1) Rf 0.51.

Example 5 4-Amino-3,5-dichloro-u-[[[6-[[6-(2-pyrimidinyl)hexyl]oxyJhexyllamino]~ methyl]benzenemethanol

A mixture of Intermediate 2 (0.669), 2-16-[ (6-bromohexyl)oxy] hexyl]pyrimidine (0.66qg), DEA (0.64m2) and DMF (l4m2) was heated at 90% for 4h, cooled and evaporated in vacuo. The oily residue was purified by FCC with System B (94:5:1) to give a product (705mg), which was dissolved in methanol (7m2) and fumaric acid (85mg) added.

The solution was evaporated in vacuo and the residue triturated with dry ether causing crystallisation, then recrystallised from isopropanol (7m%). The hygroscopic crystals were rapidly collected by

Filtration and partitioned between ethyl acetate (75mg) and 8% sodium bicarbonate solution (25mf). The organic phase was dried end evaporated in vacuo to give a gum which was further purified by FCC eluting with System B (96:3:1 - 94:5:1) to give a gum. Trituration with hexane afforded the title compound as a colourless powder (320mg) m.p. 55-570.

Analysis Found: €,59.5; H,7.65 N,11.4; Cl1,14.8.

C,,H36C1,N, 0, requires C,59.6; H,7.5; N,11.6; C1,14.7%. 35 .

Example 6 4-Amino-3,5-dichloro-a-[[[6-[[6-(5-pyrimidinyl)hexylloxyJhexylJamino}- methyl ]benzenemethanol

Intermediate 2 (1.33g) and S5-[6-[(6-bromohexyl)oxylhexyl] ; 5 pyrimidine (1.32g) were dissolved in DMF (22m) containing DEA es (1.02ml) and heated at 100-1100 for 2h, cooled and cvaporated in a vacuo. The residue was purified by FCC. Elution with toluene and tl System B (97:2:1-94:5:1) followed by System B (89:10:1) gave the desired product (380mg) followed by mixed fractions. The mixed fractions were dissolved in methanol (ém%) and fumeric acid (80mg) added, then the solution evaporated in vacuo. The oily residue was slowly recrystallised from isopropanol (~10mf%) to afford the hygroscopic fumarate salt, which was taken up in methanol (~3mf%) and partitioned between 8% sodium bicarbonate solution (15m2) and ethyl acetate (50me). The organic phase was dried and evaporated in vacuo to give the product as a gum, which wes combined with the desired product obtained above. Trituration with hexane afforded the title ) compound as a pale yellow powder (620mg) m.p. 59-619, t.l.c. (System A oo 80:20:1) RF 0.47. : methyllbenzenemethanol

A solution of 4-amino-3,5-dichloro-a-[[[6-[2-(2-benzoxazolyl) ethoxy Jhexyl]l(phenylmethyl)aminolmethyllbenzenemethanol (1.099) in ethanol (25m) containing conc. hydrochloric acid - ethanol (1:9, 1.78m1) was added to a pre-hydrogenated suspension of 10% palladium on carbon (50% aqueous paste, 0.659) and hydrogenated at room temperature and pressure, then filtered through hyflo and evaporated in vacuo.

The residue was partitioned between 8% sodium bicarbonate (25m2) and ethyl acetate (50m) and the organic phase dried and evaporated in i vacuo to a semi solid. Purification by FCC over silica (Merck 60) eluting with System B (97:2:1 + 94:5:1) afforded the title compound as a gum, which crystallised after trituration with hexane to a white ; 35 solid (613mg) m.p. 85-879.

Analysis Found: C,59.1; H,6.2; N,8.85; C1,15.25; . €,3",4C1,N;04 requires C,59.2; H,6.3; N,9.0; Cl1,15.2%.

4-Amino-3,5-dichloro-a-[1-[[6-[2-(2-pyridinyl)ethoxylhexyllamino]- ethyl]lbenzenem:thanal, (E)-butenedioate salt (2:1) Co

A solution of 4-amino-3,5-dichloro-a~[1-[(phenylmethyl)[6-[2-(2- pyridinyl)ethoxyJhexyl]amino ethyl lbenzenemethanol (0.67g) in ethanol oo ~ (25m2) containing conc. hydrochloric acid-ethanol (1:9, 2.33m1) was 5 : . added to a prehydrogenated suspension of 10% palladium on charcoal “ "(50% aqueous paste, lg) in ethanol (20m) and hydrogenated at room temperature and pressure. The mixture was filtered through hyflo and evaporated in vacuo to an oil which was partitioned between 8% sodium bicarbonate (20mf) and ethyl acetate (60mf). The orgsnic phase was dried end evaporated in vacuo and the residue purifed by FCC eluting with System 8 (89:10:1) to give a gum. A solution of the gum in : methanol (15mt) was treated with fumaric acid (60mg) and evaporated in vacuo. The residue was triturated with dry ether to afford the title ' " compound as a colourless powder (381mg) m.p. 137-1390. . Analysis Found: C,56.8; H,6.9; N,B8.2; C1,13.9;

EE €,,H3,CL,N50,.0.5C,H,0, .0.5H,0 requires : C,56.8; H,6.75; N,8.3; C1,13.9%

Co Example 9 4-Amino-3,5-dichloro-a-[[[6-[1-methyl-3-(2-pyridinyl)propoxyJhexyll- amino]methyl]benzenemethanol, (E)-butenedicate salt (2:1) 4-Amino-3,5-dichloro-a-[[[6-[1-methyl-3-(2-pyridinyl) propoxy Jhexyl](phenylmethyl)aminoJmethylJbenzenemethanol (0.85g) was : hydrogenated according to the method of Example 8. FCC purification of the residue obtained from the ethyl acetate extract eluting with

System B (96:3:1 » 94:5:1) gave an oil (590mg). A solution of this 0il in ethanol (10m%) was treated with fumaric acid (75mg) and evaporated in vacuo. Trituration with hexane afforded the title compound as a colourless powder (585mg) m.p. 113-1150. . Analysis Found: €,57.8;4,6.6;N,7.9;C1,13.6.

CpqHy3CL,N50,.0.5C, 11,0, .0.4H,0 requires C,57.8;H,6.9;N,8.15C1,13.65%. ’ 35 4 ; : ! 3

Example 10 4-Amino-3,5-dichloro-a-[[[6-[[6-(pyrazinyl)hexyl]JoxyJhexyllamino]- methyl]benzenemethanol

A solution of 4-amino-a-(aminomethyl)-3,5-dichlorobenzenemethanol (1.2g), DEA (0.72m2) and (6-[(6-bromohexyl)oxylhexyllpyrazine (1.16qg) in DMF (10m) was heated at 100-1100 for 3h. The resulting dark

Fl a solution was evaporated in vacuo and the residue purified by FCC

Se : eluting with System B (96:2:2593:5:2) to give the title compound as

Sr pale yellow crystals (0.92g), m.p. 60-630.

Analysis Found: €,59.0; H,7.2; N,11.5; C1,15.15.

CauH36CL5N,0,.0.05H,0 requires €,59.5; H,7.5; N,11.6; C1,14.65%.

Example 11 4-Amino-3,5-dichloro-a-[[[6-[3-(2-thiazolyl)propoxy Jhexyllamino] methyl]benzenemethanol, (E) butenedioate salt (2:1)

A mixture of 4-amino-a-(aminomethyl)-3, S-dichlorobenzenemethanol (800mg), 2-[[ (6-bromohexy1)oxy Jpropyllthiazole (739mg) and DEA (390mg) in dry DMF (10mg) was heated at 80° for 2h under nitrogen. The : solvent was evaporated and the residue purified by FCC eluting with : 20 ,' System B (95:5:1) to give the base as a pale yellow oil (615mg). A : solution of the oil in methanol (5m%) was treated with a solution of fumaric acid (BOmg) in methanol (5mg). The solvent was, evaporated off cee

So and the residue triturated under ether (10mg) to give the title compound as a white powder (560mg), m.p. 113-40,

Analysis Found: C,51.9; H,5.9; N,8.0; 5,6.0; C1,13.2

C20H29C1,N30,5.0.5C,H,0, .0.5H,0 requires

C,51.5; H,6.3; N,B.2; §,6.2; C1,13.8%.

Example 12 4-Amino-3,5-dichloro-a-[[[6-[{6-(2-quinolinyl)hexylJoxylhexyllaminol- methyl]benzenemethanol

A solution of 2-[6-[(6-bromohexyl)oxyl-1-hexynyllquinoline (1.96g) in ethanol (100m&) was hydrogenated over pre-reduced 10% palladium oxide { on charcoal catalyst (750mg). The catalyst was removed by filtration . through hyflo end the filtrate eveporated to a brown oil (1.329). A solution of 4-amino-«-(aminomethyl)-3,5-dichlorobenzenemethanol ; (1.05g) and DEA (0.429) in DMF (30mR) was treated at 900 with a solution of the above brown oil (1.06g) in DMF (20m%). The solution was heated to 90-1009 under nitrogen for 3h, cooled and evaporated in vacuo to a gum. The residue was purified by FCC eluting with System B

(98:2:1) to give a pale yellow oil which was triturated with hexane to produce the title compound as a cream coloured powder (1.049). m.p. 62.3 - 64.70. : Analysis Found: £,65.45; H,7.7; N,7.8; Cl1,13.9. . NL U5 C,qH49C1,N30, requires C,65.40; H,7.4; N,8.0; C1,13.3%. nA : Example 13

GAA ©" 4-Amino-3,5-dichloro-a-[[[6-[[6-(2-pyridinyl)hexylJoxylhexyllamino]

Bre oo ~ methyllbenzenemethanol, (E)-butenedioate salt (2:1) hE 110 A solution of 4-amino-3,S5-dichloro-a-{(phenylmethyl)[6-[[6-(2- na co pyridinyl)-5-hexynylJoxylhexyllaminolmethyl Jbenzenemethanol (1.65g) in " - ethanol (30m) was hydrogenated over pre-reduced 10% palladium oxide . on charcoal catalyst (650mg) in ethanol (10m) containing hydrochloric . acid (conc. hydrochloric scid:ethanol 1:9, 5.27ml). The mixture was filtered through hyflo and evaporated in vacuo to give an oil which was dissolved in ethyl acetate (120mf) and washed with 8% sodium bicarbonate solution (100m2). The organic phase was dried and evaporated in vacuo to an oil and purified by FCC eluting with System

A (90:10:1 » B80:20:1) to give a pale brown oil (750mg). This was dissolved in methanol (20m2) and a solution of fumaric acid (91mg) in methanol (10m) was added. The solvent was evaporated to leave the title compound as a pale brown powder which was recrystallised from isopropanol and triturated under ether to give the title compound as a pale brown powder (490mg), m.p. 100-1020. :

Analysis Found: C,59.1;H,7.3;N,7.5;C1,12.7. *

C,5H37C1,N30,.0.5C,H,0,.0.5H,0 requires C,59.0;H,7.3;N,7.65;C1,12.9%.

Example 14 oo 4-Amino-3,5-dichloro-a-[[[6-[3-(2-quinolinyl)propoxyJhexyllamino] methyl]benzenemethanol, (E)-butenedioate salt (2:1) : A solution of 4-amino-a-{sminomethyl)-3,5-dichlorobenzenemethanol

I. (0.769), DEA (0.65m%) in DMF (12mf) was treated with 2-[3-[(6- . 3 bromohexyl)oxy Jpropyllquinoline (0.886g), heated at 115-1200 for 2h, : oo . cooled and evaporated in vacuo. The residue was purified by FCC : : 35 eluting with System B (96:2:2+94:5:1) to give the free base of the

Lo title compound (542mg), m.p. 44-49%. This was dissolved in methanol

(3 « voy (6m) and fumaric acid (64mg) added. The methanol was removed in

Yacuo and the residue recrystallised from isopropanol (15m) to give the title compound as colourless needles (517mg), m.p. 121-122.50,

Analysis Found: C,60.65H,6.2;N,7.5;C1,12.8.

C26133C15N;30,.0.5€,1,0,.0. 51,0 requires C,60.3;H,6.5;N,7.5;C1,12.7%

The following are examples of suitable formulations of compounds of the invention. The term 'active ingredient' is used herein to : represent a compound of the invention.

Tablets (Direct Compression) mg/tablet

Active ingredient 2.0 . Microcrystalline cellulose USP 196.5

Magnesium Stearate BP 1.5

Compression weight 200.0

The active ingredient is sieved through a suitable sievé, blended with the excipients and compressed using 7mm diameter punches.

Tablets of other strengths may be prepared by altering the ratio of active ingredient to microcrystalline cellulose or the compression weight and using punches to suit.

The tablets may be film coated with suitable film forming materials, such ag hydroxypropylmethylcellulose, using standard : techniques. Alternatively, the tablets may be sugar coated.

Metered Dose Pressurised Aerosol (Suspension Aerosol) mg/metered dose Per can

Active ingredient micronised 0.100 26.40mg

Oleic Acid BP 0.010 2.64mg

Trichlorofluoromethane BP 23.64 5.67¢g

Dichlorodifluoromethane Bp 61.25 14.709 . Co . - 35 - . Rd

<

The active ingredient is micronised in a fluid energy mill to a fine particle size range. The oleic acid is mixed with the trichlorofluoromethane at a temperature of 10-15% and the micronised : drug is mixed into the solution with a high shear mixer. The : 5 suspension is metered into aluminium aerosol cans and suitable

Le So metering valves delivering 85mg of suspension are crimped onto the oe cans and the dichlorodifluoromethane is pressure filled into the cans through the valves. '

Inhalation Cartridges ‘ mg/cartridge

Active ingredient micronised 0.200 ‘

Lactose BP to 25.0 i . 15 The active ingredient is micronised in a fluid energy mill to a Co i fine particle size range prior to blending with normal tebletting . grade lactose in a high energy mixer. The powder blend is filled into

No. 3 hard gelatin capsules on a suitable encapsulating machine. The contents in the cartridges are administered using a powder inhaler such as the Glaxo Rotahaler. t : { oo - 36 - Co

Claims (11)

WE CLAIM

1. A compound of the formula (I) 2 TN co HoN TR) prempenzockz et _ : / OH R? cl (1) or a physiologically acceptable salt or solvate thereof, wherein Q represents a chlorine atom; X represents a Ci_g2lkylene chain, and Y represents a Ci_gdlkylene chain with the proviso that the sum total or carbon atoms in the chains X and Y is not more than 10, and the chain CH,Y may be optionally substituted by one Cy-32tkN group; R represents a hydrogen atom or a C,_3alkyl group; R! and RZ each represent a hydrogen atom; and Het represents a benzoheteroaryl or a monocyclic heteroaryl group wherein the heteroaryl group is 5 or 6 membered and contains 1, 2 or 3 hetero atoms, one of which is a nitrogen atom and the other(s) is {are) nitrogen, oxygen or sulphur atom(s), and the group Het may optionally be substituted by one or two groups selected from Ci-q2tkyl, with the proviso that when Het represents a pyridyl group optionally substituted by one or two groups selected from Cq_3alkyl and Y represents a :

Ci.q21kylene chain, then, R represents a Cy-32Tkyl group and/or the chain -CH,Y- is substituted by one Cy.321ky1 Co group.

2. A compound according to claim 1 in which the sum total of carbon atoms in the chains X and Y is 4, 5, 6, 7, 8 or 9.

3. A compound according to claim 1 in which X represents -(CH,) 4 and y represents -(CHy),s -(CHy) 4- or -(CHy) =.

4. A compound according to claim 1 in which R represents a hydrogen atom.

5. A compound according to claim 1 in which Het represents So , , a group selected from pyrimidinyl, pyrazinyl, triazinyl, } } thiazolyl, quinolinyl, benzimadazolyl, benzothiazolyl, benzoxazolyl and pyridyl.

6. A compound according to claim 1 in which Het represents a pyrimidinyl or thiazolyl group.

7. 4-Amino-3,5-dichloro-a-[[[6-[3-(2-thiazoly1)propoxy]-hexy1]- amino Jmethyl]benzenemethanol; or a physiologically acceptable salt or solvate thereof.

8. A pharmaceutical composition for therapy or prophylaxis of a disease associated with reversible airways obstruction , which comprises an effective amount to alleviate said disease of one compound of formula (1) as defined in claim 1 or a ‘ physiologically acceptable salt or solvate thereof, together with a physiologically acceptable carrier or excipient.

9. A method of therapy or prophylaxis of a disease associated with reversible airways obstruction in a patient, which comprises administering to said patient an effective amount : to alleviate said disease of a compound of formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof.

10. A pharmaceutical composition according to claim 8 wherein said disease associated with reversible airways obstruction is asthma or chronic bronchitis.

11. A method of therapy or prophylaxis according to claim 9 wherein said disease associated with reversible airways obstruction is asthma or chronic bronchitis. LAWRENCE HENRY CHARLES LUNTS Inventor